Our proposed research has been primarily aimed at testing and examining physical models for enamel demineralization and enamel reactions in general with particular emphasis on those situations that bear on the initiation of dental caries and the actions of therapeutic agents for caries. The general theoretical approach involves quantitatively taking into account the effects of all diffusion processes, all chemical equilibria and reactions, and all other physicochemical factors. Thus, in essence, our research approach has been one based on a "systems engineering" concept. The resulting theoretical relationships for the various models are being examined in detail with experimental demineralization data obtained with both dental enamel and synthetic mineral (especially, hydroxyapatite) under various conditions. Very recent breakthroughs have led to the development of a comprehensive model for dental enamel demineralization based upon two dissolution "sites" for the apatite crystals in the enamel matrix. This model has been totally consistent with virtually all experimental observations including the chemical kinetics data (pH, common ion, foreign ion and fluoride effects), single crystal morphology changes, and gross morphology changes (e.g., zonal dissolution or, clinically, "white spot" formation). Current efforts are to investigate and apply this model in the evaluation of several foreign ion effects (Sr, Mg, Ti, Zn, Ba, Cd, Pb, Fe, and Sn), dissolution rate inhibitors (alkylamines, diphosphonates, polymers and polyelectrolytes), and the dissolution rate behavior in EDTA and in bicarbonate solutions.